Importance Of Genetic Variability Research Articles

Genotypic Analysis of ABCA4 Coding Sequence in Thai Patients with Stargardt Disease

Objective: To study the mutational spectrum of the ABCA4 gene in Thai patients with Stargardt disease. Materials and Methods: DNA sequencing of all 50 exons of the ABCA4 gene was performed in nine Thai patients with clinically diagnosed Stargardt disease. Results: Amino acid sequence variation in the ABCA4 gene was found in five patients. Six missense mutations, c.71G>A, c.635G>A, c.1268A>G, c.3626T>C, c.4283C>T, and c.5761G>A, previously associated with Stargardt disease, were identified in our cohort. The variant c.1268A>G was the most prevalent in our study. Conclusion: In this cohort, only 56% of Thai Stargardt patients had missense mutations in the ABCA4 gene. Mutations in the non-coding regions of the ABCA4 or mutations in other genes may be responsible for Stargardt phenotypes in the remaining patients. Our findings are the first to reveal the mutational spectrum of ABCA4 leading to Stargardt disease in the Thai population and demonstrate a potential for ABCA4 screening as well as the importance of genetic variability in Thai patients with clinically suspected Stargardt disease.

Antipsychotic medication-mediated cognitive change in schizophrenia and polygenic score for cognitive ability

Cognitive symptoms of schizophrenia are reported to be minimally responsive to treatment with antipsychotic medications, though variability exists and many prior studies have significant confounds. Here, we examined the response of cognitive symptoms to antipsychotic medications in 71 inpatients with schizophrenia on and off antipsychotic medications in a blinded, placebo-controlled, cross-over study design. Patients received either antipsychotic medication monotherapy or placebo for 4–6 weeks before switching conditions. Neuropsychological testing, including working memory, intelligence, episodic memory, and verbal fluency tests, was administered during each condition. Additionally, we assessed whether polygenic scores for cognitive ability (PGScog) related to variability in antipsychotic medication-induced changes in cognitive performance. Overall, significant changes in cognition were not observed in response to medications (p's > 0.05) except for in episodic memory (p = 0.01), which showed a medication-related improvement. Some antipsychotic medication-related cognitive changes were associated with genetic predisposition to cognitive ability: PGScog showed positive correlations with medication-induced improvements in verbal list learning (p = 0.02) and category fluency (p = 0.03). Our primary results reinforce the notion that in general, cognitive measures are minimally responsive to antipsychotic medication. However, PGScog results suggest that genetic variation may influence the ability of current treatments to affect cognitive change within this patient population. This study underscores the need for development of novel treatment options specifically targeting cognitive symptoms as well as the importance of genetic variability in treatment response for patients with schizophrenia.

Motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function

Dopaminergic neurotransmission plays a pivotal role in appetitively motivated behavior in mammals, including humans. Notably, action and valence are not independent in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward. We have previously observed that the carriers of the DRD2/ANKK1 TaqIA A1 allele, that has been associated with reduced striatal dopamine D2 receptor expression, showed a diminished learning performance when required to learn response inhibition to obtain rewards, a finding that was replicated in two independent cohorts. With our present study, we followed two aims: first, we aimed to replicate our finding on the DRD2/ANKK1 TaqIA polymorphism in a third independent cohort (N = 99) and to investigate the nature of the genetic effects more closely using trial-by-trial behavioral analysis and computational modeling in the combined dataset (N = 281). Second, we aimed to assess a potentially modulatory role of prefrontal dopamine availability, using the widely studied COMT Val108/158Met polymorphism as a proxy. We first report a replication of the above mentioned finding. Interestingly, after combining all three cohorts, exploratory analyses regarding the COMT Val108/158Met polymorphism suggest that homozygotes for the Met allele, which has been linked to higher prefrontal dopaminergic tone, show a lower learning bias. Our results corroborate the importance of genetic variability of the dopaminergic system in individual learning differences of action–valence interaction and, furthermore, suggest that motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function.

Genetic Variability of Two Leaffooted Bugs, Leptoglossus clypealis and Leptoglossus zonatus (Hemiptera: Coreidae) in the Central Valley of California.

Leaffooted plant bugs (LFPBs) (Leptoglossus spp., Guérin-Méneville) (Hemiptera: Coreidae) are large seed-feeding bugs native to the Western Hemisphere. In California, several Leptoglossus spp. feed on almonds, pistachios, and pomegranate and are occasional pests. The objective of this study was to survey the different species of Leptoglossus present in almond, pistachio, and pomegranate orchards in the Central Valley of California. We used two molecular markers, amplified fragment length polymorphisms (AFLPs) and mitochondrial DNA COI, to determine the number of species or strains of each species, and to infer whether individuals of each species move and possibly interbreed with populations from the other host plants. Two species of leaffooted bugs were abundant, Leptoglossus clypealis Heidemann, and Leptoglossus zonatus (Dallas). L. clypealis was collected in almond and pistachio, while L. zonatus was found on all three host plants, but was the dominant species in pomegranate. The AFLP results indicated that L. clypealis consisted of one species, which suggests it moves between almonds and pistachios during the growing season. Mitochondrial DNA COI for L. clypealis found 1-2% divergence between sequences, and a high haplotype diversity of 0.979 with 17 haplotypes. The AFLP results for L. zonatus found two genetically divergent populations which were morphologically similar. The mtDNA COI sequences for L. zonatus were used for haplotype analysis; three haplotypes were found in California, with one haplotype shared with collections from Brazil. The importance of genetic variability and cryptic species for pest management are discussed.

Genetic Variation and Structure in Remnant Population of Critically Endangered Melicope zahlbruckneri

The distribution and amount of genetic variation within and between populations of plant species are important for their adaptability to future habitat changes and also critical for their restoration and overall management. This study was initiated to assess the genetic status of the remnant population of Melicope zahlbruckneri–a critically endangered species in Hawaii, and determine the extent of genetic variation and diversity in order to propose valuable conservation approaches. Estimated genetic structure of individuals based on molecular marker allele frequencies identified genetic groups with low overall differentiation but identified the most genetically diverse individuals within the population. Analysis of Amplified Fragment Length Polymorphic (AFLP) marker loci in the population based on Bayesian model and multivariate statistics classified the population into four subgroups. We inferred a mixed species population structure based on Bayesian clustering and frequency of unique alleles. The percentage of Polymorphic Fragment (PPF) ranged from 18.8 to 64.6% for all marker loci with an average of 54.9% within the population. Inclusion of all surviving M. zahlbruckneri trees in future restorative planting at new sites are suggested, and approaches for longer term maintenance of genetic variability are discussed. To our knowledge, this study represents the first report of molecular genetic analysis of the remaining population of M. zahlbruckneri and also illustrates the importance of genetic variability for conservation of a small endangered population.

β-GLUCANS CONTENT AS A PERSPECTIVE TRAIT IN THE BARLEY BREEDING FOR FOODSTUFF USE (review)

On the ground of data of foreign literature the authors consider the target utilization of barley in connection with -glucans in grain. The authors analyzed the influence of a genotype, climatic conditions and agronomic methods of plant growing on -glucans content in barley corn. The information was presented about physiologo-biochemical parameters -glucans, which may be helpful for a development of indirect estimation of breeding material. Thus, it was fixed the negative correlation between -glucans content in barley grain on the one hand and value of 1000seeds mass, amylose and starch content, ash percent, corn yield — on the other hand. The strong positive correlation was found between the content in corn of glucans, lipids, protein and the grain-unit and its hardness. The existence of such correlations makes possible the development of indirect estimation during barley breeding on heightened/reduced -glucans content in grain. It was shown, that glumaceous amylose-free varieties are more advanced agronomically (in arid climate, especially), as they are able to realize a substantial potential of yield with high content of -glucans. The authors made a conclusion about an importance of genetic variability in content of -glucans in barley grain for successful breeding on this determinant.

A Recessive Gene Variant in TGFB1 in the Donor Influences the Acute Graft Versus Host Disease Development and Impacts in the Outcome After Allogeneic Stem Cell Transplantation (Allo-SCT),

Abstract 4080After allogeneic stem cell transplantation (allo-SCT) inflammatory cytokines and other innate immune proteins interact leading to a differentiation of donor lymphocytes which will increase the inflammatory response initiating the acute graft versus host disease (aGvHD). In this cytokine storm, TGF-β is a pleiotropic cytokine with dual roles presenting beneficial and detrimental effects after allo-SCT. Depending on its interaction with other cytokines, TGF-β will inhibit differentiation of Th1 cells and cytotoxic T lymphocytes (CTLs), and will promote expansion and maintenance of T-reg cells lowering the development of aGvHD, or it will activate Th17 lymphocyte differentiation increasing aGvHD development. Previously, we found that a recessive gene variant (AA) in TGFB1 in the promoter region was associated with higher incidence of aGVHD when present in the donor in a cohort of 99 adult donor-patients pairs who underwent HLA identical sibling allo-SCT. We aimed to validate this previous association in a multicentre study consisting of 490 adults donor-patients pairs who underwent HLA identical sibling allo-SCT. All patients were diagnosed with hematological malignancies. Median age was 45 (range, 16–69), 33% were in advanced phase of disease, and 38% received a reduced intensity conditioning regimen. Association results showed that recessive AA gene variant in TGFB1 when present either in the donor or in the patient, or in both, was associated with higher aGvHD grades III-IV (19% vs 11%, p=0.039; and 22% vs 12%, p=0.049; and 22% vs 12%, p=0.04, respectively). This variant in the donor also impacted in a higher transplant related mortality (42% vs 27%, p=0.019), influencing in both, a lower disease free survival (33% vs 44%, p=0.03, OR=1.5, p=0.03) and lower overall survival (43% vs 52%, p=0.011, OR=1.4, p=0.049). Further, we performed functional studies in 180 blood donors analyzing the expression of Th1/Th2 cytokines after phytohemagglutinin (PHA) and cytomegalovirus exposure to find out if the presence of this variant influenced in the inflammatory response. We found that recessive AA gene variant in TGFB1 was associated with higher IFNγ production (1265 pg/mL vs 1365 pg/mL vs 1471 pg/mL, p=0.02, respectively, for GG dominant variant, GA heterozygous variant, and AA recessive variant). Finally, we performed real time PCR at basal levels in blood donors to find out if this variant was associated with a differential expression of TGFB1, and we observed a non significant reduction of the expression in the recessive AA variant compared to the dominant GG variant. It is well known that increased IFNγ serum levels are associated with the severity of aGVHD and that IFNγ is crucial during the development of aGvHD initiating the proinflammatory response. These results indicate the importance of genetic variability in the cells of the donor in TGFB1 in the development of GvHD and the possible role of this variant in the IFNγ production. The knowledge of this variant in the donor might help to the prevention of aGvHD after allo-SCT. Disclosures:No relevant conflicts of interest to declare.

The importance of genetic variability and population differentiation in the Eurasian lynx Lynx lynx for conservation, in the context of habitat and climate change

1 The Eurasian lynx Lynx lynx occupies a variety of environmental and climatic conditions, and the majority of present-day European populations have either recovered from severe demographic bottlenecks, or are living in fragmented habitat. These factors may have affected the genetic variability of lynx populations. We summarize available data on genetics, population status and ecology of these felids to shed light on the pattern and mechanisms behind their genetic variability and population differentiation in Europe. 2 Genetic studies conducted so far, based on mtDNA and microsatellites, have shown that the Eurasian lynx has low to moderate genetic variability. Variability is lowest in the north (Scandinavian bottlenecked population), but is also low in the Carpathian region. A trend towards loss of genetic variation has been noted in fragmented and reintroduced populations. Genetically, the populations are highly differentiated from each other. 3 There are clear relationships between the pattern of lynx genetic variability, differentiation between the populations, and such factors as population history (demographic bottlenecks), social interactions and habitat fragmentation. The genetic divergence between lynx populations is also strongly correlated with the depth and duration of snow cover. 4 Our review provides evidence that the lynx is undergoing significant genetic differentiation, due to several factors. To enable better planning of conservation programmes for the Eurasian lynx, researchers should identify the Evolutionarily Significant Units among its populations, using different classes of molecular markers.

Plant resource-use strategies: the importance of phenotypic plasticity in response to a productivity gradient for two subalpine species.

Functional traits are indicators of plant interactions with their environment and the resource-use strategies of species can be defined through some key functional traits. The importance of genetic variability and phenotypic plasticity in trait variations in response to a common environmental change was investigated in two subalpine species. Two species with contrasted resource-use strategies, Dactylis glomerata and Festuca paniculata, were grown along a productivity gradient in a greenhouse experiment. Functional traits of different genotypes were measured to estimate the relative roles of phenotypic plasticity and genetic variability, and to compare their levels of phenotypic plasticity. Trait variability in the field for the two species is more likely to be the result of phenotypic plasticity rather than of genetic differentiation between populations. The exploitative species D. glomerata expressed an overall higher level of phenotypic plasticity compared with the conservative species F. paniculata. In addition to different amplitudes of phenotypic plasticity, the two species differed in their pattern of response for three functional traits relevant to resource use (specific leaf area, leaf dry matter content and leaf nitrogen content). Functional trait variability was mainly the result of phenotypic plasticity, with the exploitative species showing greater variability. In addition to average trait values, two species with different resource-use strategies differed in their plastic responses to productivity.

Genomic polymorphisms of the innate immune system and allogeneic stem cell transplantation

Allogeneic stem cell transplantation (allo-HSCT) is largely employed for treating patients affected by many hematological disorders, but despite the considerable improvement in the treatment of its complications, graft-versus-host disease and infections remain important causes of morbidity and mortality. Innate immunity is crucial in the immune defense against infections after allo-HSCT, and in the biological reactions leading to graft-versus-host disease. Thus, the innate immune system plays an important role in allo-HSCT clinical outcome. It is known now that cytokine gene polymorphisms greatly influence the outcome of allo-HSCT. In addition, genetic variability of some pattern-recognition receptors and antimicrobial peptides represent a promising field to be researched for allo-HSCT impact. Furthermore, more recent work suggests the importance of genetic variability between donor and recipient in the killer cell immunoglobulin-like receptors of the natural killer cells on the allo-HSCT outcome. This article discusses the main cytokines and innate immune gene polymorphisms influencing allo-HSCT outcome, presents new innate immune genes with promising expectations and points at the importance of genetic variability in natural killer cells in allo-HSCT outcome.

Beyond TPMT: genetic influences on thiopurine drug responses in inflammatory bowel disease.

Azathioprine and 6-mercaptopurine are widely used in the management of inflammatory bowel disease (IBD). However, approximately 25% of IBD patients experience toxicity, and up to 10% show resistance to these thiopurine drugs. The importance of genetic variability in determining thiopurine toxicity was first recognized over 25 years ago with the discovery of the thiopurine S-methyltransferase (TPMT) polymorphism and the occurrence of azathioprine-induced myelosuppression in TPMT-deficient patients. In the intervening period, TPMT has become the foremost example of pharmacogenetics, and TPMT deficiency represents one of the few pharmacogenetic phenomena that have successfully made the transition from the research laboratory to diagnostics. While TPMT activity predicts some cases of myelosuppression, deficiency in this enzyme is neither predictive of other adverse drug reactions, nor resistance to thiopurine therapy. As myelosuppression only accounts for approximately 2.5% of adverse reactions in IBD patients, researchers are increasingly turning their attention to other enzymes involved in thiopurine metabolism to find molecular explanations for intolerance and resistance to azathioprine and 6-mercaptopurine. In this review, we summarize the current state of knowledge with regards to TPMT, and also explore genetic variability, beyond TPMT, that may contribute to thiopurine response in IBD patients.

Genetic variance contributes to naltrexone-induced inhibition of sucrose intake in inbred and outbred mouse strains

The study of genetic variance in opioid receptor antagonism of sucrose and other forms of sweet intake has been limited to reductions in sweet intake in mice that are opioid receptor-deficient or lacking either pre–pro-enkephalin or beta-endorphin. Marked genetic variance in inbred mouse strains has been observed for sucrose intake across a wide array of concentrations in terms of sensitivity, magnitude, percentages of kilocalories consumed as sucrose and compensatory chow intake. The present study examined potential genetic variance in systemic naltrexone's dose-dependent (0.01–5 mg/kg) and time-dependent (5–120 min) ability to decrease sucrose (10%) intake in eleven inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) mouse strains. A minimum criterion sucrose intake (1 ml) under vehicle treatment, designed to avoid “floor effects” of antagonist treatment was not achieved in three (A/J, AKR/J, CBA/J) inbred mouse strains. Marked genetic variance in naltrexone's ability to inhibit sucrose intake was observed in the remaining strains with the greatest sensitivity observed in the C57BL/10J and C57BL/6J strains, intermediate sensitivity in BALB/cJ, C3H/HeJ, CD-1 and DBA/2J mice, and the least sensitivity in 129P3/J, SWR/J and SJL/J strains with a 7.5–36.5 fold range of greater effects in the ID50 of naltrexone-induced inhibition in C57BL/10J relative to the three less-sensitive strains across the time course. Naltrexone primarily affected the maintenance, rather than the initiation of intake in BALB/cJ, CD-1, C3H/HeJ, DBA/2J and SJL/J mice, but significantly reduced sucrose intake at higher doses across the time course in C57BL/6J, C57BL/10J and 129P3/J mice. Whereas SWR/J mice failed to display any significant reduction in sucrose intake at any time point following any of the naltrexone doses, naltrexone's maximal magnitude of inhibitory effects was small (35–40%) in 129P3/J and SJL/J mice, moderate (∼50%) in BALB/cJ, C3H/HeJ, CD-1 and DBA2/J mice, and profound (70–80%) in C57BL/6J and C57BL/10J mice. Indeed, the latter two strains displayed significantly greater percentages of naltrexone-induced inhibition of sucrose intake than virtually all other strains. These data indicate the importance of genetic variability in opioid modulation of sucrose intake.

The Genetic Determinants of Renal Impairment Following Cardiac Surgery

Cardiac surgery is frequently performed, and acute renal dysfunction is a common adverse event following this procedure. Cardiac surgery-related renal injury independently predicts longer hospital stays and greater rates of morbidity and mortality. Although much work has been completed toward better understanding of this phenomenon, the state of knowledge concerning surgery-related renal injury remains limited. Currently, there is no effective paradigm to identify patients who are at risk for this condition; the specific mechanisms of renal injury during surgery are incompletely understood; and few therapies exist to prevent or treat this phenomenon. To better understand this common clinical problem, recent research has focused on the importance of genetic variability within the physiological and patho-physiological systems that underlie renal dysfunction following cardiac surgery. Emphasizing the importance of using genetics to elucidate molecular mechanisms of this disease, this article reviews the current literature on genetic polymorphisms and post cardiac surgery-related renal dysfunction.

S-50-3 - Narcotic antagonists in the treatment of alcoholism

The study of genetic variance in opioid receptor antagonism of sucrose and other forms of sweet intake has been limited to reductions in sweet intake in mice that are opioid receptor-deficient or lacking either pre–pro-enkephalin or beta-endorphin. Marked genetic variance in inbred mouse strains has been observed for sucrose intake across a wide array of concentrations in terms of sensitivity, magnitude, percentages of kilocalories consumed as sucrose and compensatory chow intake. The present study examined potential genetic variance in systemic naltrexone's dose-dependent (0.01–5 mg/kg) and time-dependent (5–120 min) ability to decrease sucrose (10%) intake in eleven inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) mouse strains. A minimum criterion sucrose intake (1 ml) under vehicle treatment, designed to avoid “floor effects” of antagonist treatment was not achieved in three (A/J, AKR/J, CBA/J) inbred mouse strains. Marked genetic variance in naltrexone's ability to inhibit sucrose intake was observed in the remaining strains with the greatest sensitivity observed in the C57BL/10J and C57BL/6J strains, intermediate sensitivity in BALB/cJ, C3H/HeJ, CD-1 and DBA/2J mice, and the least sensitivity in 129P3/J, SWR/J and SJL/J strains with a 7.5–36.5 fold range of greater effects in the ID50 of naltrexone-induced inhibition in C57BL/10J relative to the three less-sensitive strains across the time course. Naltrexone primarily affected the maintenance, rather than the initiation of intake in BALB/cJ, CD-1, C3H/HeJ, DBA/2J and SJL/J mice, but significantly reduced sucrose intake at higher doses across the time course in C57BL/6J, C57BL/10J and 129P3/J mice. Whereas SWR/J mice failed to display any significant reduction in sucrose intake at any time point following any of the naltrexone doses, naltrexone's maximal magnitude of inhibitory effects was small (35–40%) in 129P3/J and SJL/J mice, moderate (∼ 50%) in BALB/cJ, C3H/HeJ, CD-1 and DBA2/J mice, and profound (70–80%) in C57BL/6J and C57BL/10J mice. Indeed, the latter two strains displayed significantly greater percentages of naltrexone-induced inhibition of sucrose intake than virtually all other strains. These data indicate the importance of genetic variability in opioid modulation of sucrose intake.

Venation Polymorphism and Genetic Variability in Drosophila melanogaster Loew

Experimental evidence indicates that phenocopy production may provide an inflated estimate of the importance of genetic variability and recombination in the production of venation phenodeviants.